Natural selection in a contemporary
human population
Sean G. Byarsa, Douglas Ewbankb, Diddahally R. Govindarajuc, and Stephen C. Stearnsa,1
a
Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520-8102; bPopulation Studies Center, University of Pennsylvania,
Philadelphia, PA 19104-6299; and cDepartment of Neurology, Boston University School of Medicine, Boston, MA 02118-2526
Edited by Peter T. Ellison, Harvard University, Cambridge, MA, and approved September 16, 2009 (received for review June 25, 2009)
Our aims were to demonstrate that natural selection is operating
on contemporary humans, predict future evolutionary change for
specic traits with medical signicance, and show that for some
traits we can make short-term predictions about our future evolu-
tion. To do so, we measured the strength of selection, estimated
genetic variation and covariation, and predicted the response to
selection for women in the Framingham Heart Study, a project of
the National Heart, Lung, and Blood Institute and Boston Univer-
sity that began in 1948. We found that natural selection is acting
to cause slow, gradual evolutionary change. The descendants of
these women are predicted to be on average slightly shorter and
stouter, to have lower total cholesterol levels and systolic blood
pressure, to have their rst child earlier, and to reach menopause
later than they would in the absence of evolution. Selection is
tending to lengthen the reproductive period at both ends. To
better understand and predict such changes, the design of planned
large, long-term, multicohort studies should include input from
evolutionary biologists.
evolutionary rates | heritability | Homo sapiens | medical traits
A re contemporary humans experiencing natural selection
and evolving in response to it? The answer to that question
depends on whom one asks. A long tradition in the medical
community (1) holds that natural selection does not operate on
contemporary human populations because medicine keeps
alive many who otherwise would have perished (2). No
evolutionary biologist would now agree with that claim, for
natural selection works through differential reproductive success
rather than simple differential survival, and individuals in con-
temporary human populations vary in lifetime reproductive
success (LRS). Selection operates on any trait that varies and is
correlated with LRS, and traits respond to selection with change
across generations if they vary genetically. But what traits is
selection operating on? Do they include the traits treated by
physicians? Previous work (e.g., ref. 3) has shown that human life
history traits, most signicantly age at rst reproduction, are
currently under selection, but evidence for selection operating
on traits of medical importance is scarce. Here, we report
estimates of natural selection, and the potential genetic response
to selection, in the women of the rst two generations of the
Framingham Heart Study (FHS) population. The traits we
analyzed include traits of medical signicance: total cholesterol
(TC), systolic blood pressure (SBP), diastolic blood pressure
(DBP), and blood glucose (GLU). We had three general aims:
rst, to correct the still widespread misconception that natural
selection is not operating on contemporary humans; second, to
make quantitative predictions about future evolutionary change
for specic traits with medical signicance; and third, to register
rmly a point of general cultural interest that follows directly
from our rst two aims: We are still evolving, and for some traits
we can make short-term predictions about our future evolution.
The Framingham Heart Study
The FHS was established in 1948 in Framingham, MA, by the
National Heart, Lung, and Blood Institute and Boston Univer-
www.pnas.org/cgi/doi/10.1073/pnas.0906199106
sity to identify factors that contribute to cardiovascular disease.
It is the longest running multigenerational study in medical
history. The people originally enrolled in the study were of pre-
dominantly European ancestry (20% United Kingdom, 40%
Ireland, 10% Italy, 10% Quebec). The original cohort (n =
5,209) has been examined every 2 years, a total of 29 times
between 1948 and 2008. The offspring cohort (n = 5,124) has
been examined approximately every 4 years, a total of eight times
between 1971 and 2008 (4). There is also a third generation
cohort (n = 4,095) that is not included in this study because many
in it have not yet completed reproduction. At each examination
many physical and blood chemistry traits are measured and a
questionnaire is administered, yielding data on >70 traits. Data
are deidentied by the FHS and delivered to the National
Institutes of Health dbGaP database, from which we down-
loaded them for analysis. In this study, we use only the data on
individuals who were measured three or more times.
Measuring Selection in a Multicohort Medical Study
Natural selection has been measured many times in natural
populations of animals and plants (5) using methods inspired by
Robertson (6), developed by Lande and Arnold (7), and rened
by Janzen and Stern (8), Hereford et al. (9), and others. To apply
those methods to contemporary human populations requires
consideration of several special features of data on humans.
Some, such as cultural variation related to education, smoking,
and medication, we dealt with as covariates. Others could in
principle be measured on natural populations of animals and
plants but in practice often are not; these include repeated
measures on individuals that establish the developmental tra-
jectories of multiple traits with age and long-term observations
of populations across several generations that reect secular
demographic trends. Both make the measurement of traits more
complex: at what age and in what portion of a secular trenda
change in conditions across time rather than ageshould the
expression of the trait be measured? The solution we chose was
to calculate the response surface of each trait for age and time
and to express the measurement of that trait for each individual
as an average deviation from that surface (e.g., Fig. 1). Thus, for
several traits we asked whether through their adult years indi-
viduals tended to have higher or lower values than other
individuals of the same age measured in the same year. Because
many individuals have been measured repeatedly in the FHS, the
response surface can be estimated accurately. And how should
This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences,
Evolution in Health and Medicine held April 23, 2009, at the National Academy of Sciences
in Washington, DC. The complete program and audio les of most presentations are available
on the NAS web site at www.nasonline.org/Sackler_Evolution_Health_Medicine.
Author contributions: D.R.G. and S.C.S. designed research; S.G.B. performed research;
S.G.B. and D.E. analyzed data; and D.R.G. and S.C.S. wrote the paper.
The authors declare no conict of interest.
This article is a PNAS Direct Submission.
1
To whom correspondence should be addressed. E-mail: stephen.stearns@yale.edu.
This article contains supporting information online at www.pnas.org/cgi/content/full/
0906199106/DCSupplemental.
PNAS | January 26, 2010 | vol. 107 | suppl. 1 | 17871792
 Original Coho
Offspring Cohort
Total choles

rt
300

250
terol (mg/10

200

150
0ml)

2000
60
Ye 1990
ar 50
m 1980
ea 40
su 1970
re e
d Ag
1960 30

20
Fig. 1. TC between the ages of 20 and 60, 19552003. Because the measure-
ment of TC changes with the age of the individual and the year of measure-
ment, we tted a surface to all measurements, calculated the residuals of all
of the measurements for each individual from this surface, and expressed the
trait measurement as a single value: the average of the residuals. We only used
individuals who had been measured at least three times (n = 2,227 women
measured 16,516 times for TC, with one individuals measures from each
cohort added for reference).
Fig. 3. Plot of average cholesterol values against LRS. Residuals from the
surface in Fig. 1 were converted back to the original metric by adding the
global mean to each value and then averaged to yield a single average residual
estimate for each woman. A cubic spline [using glms40 (25)] was then tted to
these residuals, which have the effects of age and year of measure removed,
to give a visual impression of the variation in the data and the strength of
selection. The cubic spline is not the linear selection gradient. Dashed lines
are 1 SE of tness associations (solid line).

one express relative LRS in a population that goes through a effects are mediated by the phenotypic variance/covariance
baby boom and a baby bust? We asked whether an individual had matrix P (Table 2).
relatively high LRS compared with others bearing children Second, the multitrait response to selection also depends on
during the same time period. To do so we divided the population direct and indirect effects of inheritance. Selection differentials
into six periods of differing average LRS by year of birth and will have no long-term consequences if the traits are not passed
expressed the tness of women relative to the average for their to the next generation. The direct effects on the response are
year of birth (Fig. 2). determined by the additive genetic variances of the individual
traits; these are the diagonal elements in the genetic variance
Measuring Evolutionary Change covariance matrix G (Table 3). The indirect effects are mediated
To study evolutionary change, one conceives of the process as by the off-diagonal elements of that matrix, the genetic covari-
occurring in two steps. First, selection acts through differences ances. Inheritance can either be genetic or cultural. We are not
in LRS. With multitrait phenotypes there are both direct effects able to fully differentiate the effects of genes and culture with
on the individual traits and indirect effects mediated by the these data.
phenotypic correlations among the traits. Thus, a trait may be Selection Gradients
favored by selection only because it is correlated with other traits
Selection gradients measure the extent to which individuals with
that are directly associated with greater LRS. The direct effects
a given value of a quantitative trait tend to have higher or lower
of selection are captured by the linear selection gradients ()
tness (LRS). If individuals with low levels tend to have higher
estimated as partial regression coefcients (Table 1); the indirect
LRS, then the next generation is apt to have a lower average level
of that trait (Fig. 3). We measured signicant linear selection
gradients acting to reduce total cholesterol (TC), height (HT),
SBP, and age at rst birth and to increase weight (WT) and age
e
ve
productiv

33
3.3
at menopause. These results strongly suggest that natural selec-
tion is acting on the women of the FHS through differences in
the number of children they had during their reproductive ages
Rep

28
2.8
e Re

(Table 4).
ss
s
me

In estimating the selection gradients for most of the traits, we

es
ettim

23
2.3
ce

controlled for level of education, foreign or native birth, and

uccc
e)) Life
Su

whether the individual smoked. We also estimated quadratic

S

18
1.8
terms to detect stabilizing selection (Table S1). These terms
se
(+/-- s

indicate whether a continuation of past trends will lead a trait to

Mean (+

13
1.3
change at a steady or increasing rate or whether it will tend to
level off. A total of 5.74% of the variation in LRS was explained
Me

0.8
0 8
1890 1910 1930 1950
by all factors combined (linear, quadratic, and interaction
terms). The impact of stabilizing selection is reected in our
Year
ea women
omen
o e born
bo ((+/-
/ 2 yea
years)
ears)
s) projections of evolutionary change (Table 5).
Fig. 2. LRS, by year of birth, for women in the FHS. To deal with secular
demographic change, we divided the data into six periods and divided the
Inheritance of Traits
relative reproductive success of each woman by the mean reproductive success We estimated the inheritance of traits by taking advantage of the
of the women in her group. longitudinal, multigeneration, family design for the FHS. It

1788 | www.pnas.org/cgi/doi/10.1073/pnas.0906199106 Byars et al.

Table 1. Mean values and direct and total selection gradients
TC, mg/100 mL WT, kg HT, cm SBP, mmHg DBP, mmHg GLU, mg/100 mL Age at menopause Age at rst birth

Means 2.350 1.811 2.205 2.106 1.895 1.950 1.689 1.418

0.743 0.861 3.999 0.963 0.982 0.848 1.280 1.267
P 2.841 2.581 0.533 0.323 0.526 2.554 1.981 6.940

Means, log10. , linear selection gradient from partial regressions. P , direct and indirect selection from P matrix, 1,000.

yielded pedigrees, some quite complex, for hundreds of families.
We applied a maximum-likelihood method implemented in the
software package SOLAR (24) to extract from these pedigrees
estimates of additive genetic variance and covariance. The
heritability of a trait, perhaps a more familiar term, is its additive
genetic variance divided by its total phenotypic variance, and the
genetic correlation between two traits is their additive covari-
ance divided by the square root of the product of their additive
variances. Thus, in essence we were measuring the heritabilities
of and genetic correlations between all of the traits and express-
ing them in a form suitable for evolutionary projections. This
method cannot completely discriminate between vertical cultural
transmission and genetic transmission, but the use of all degrees
of relationship, not just those between parents and offspring,
does to some degree get around this problem. Our estimates of
heritabilities were: HT, 0.84 0.01 (SE); TC, 0.61 0.02; SBP,
0.53 0.02; WT, 0.52 0.02; DBP, 0.49 0.02; age at
menopause, 0.47 0.05; GLU, 0.34 0.02; and age at rst birth,
0.09 0.02. These are similar to heritabilities found in other
studies examining phenotypic (10, 11) and life history traits (12)
in humans.
estimated for Galapagos nches and Trinidadian guppies but
comparable to those estimated for New Zealand chinook salmon
and Hawaiian mosquitosh (13). In sum, as a result of evolution
future generations of women in this population are predicted to
be slightly shorter and stouter, to have lower values for TC and
SBP, to have their rst child slightly earlier, and to reach
menopause slightly later than they would have otherwise. These
are small, gradual evolutionary changes in the middle to lower
range of those observed in contemporary populations of non-
human species.
Secular Changes
To see whether selection intensities were changing over the
period of the study, we broke the dataset down into three periods
dened by year of birth: 18921913 (n = 716), 19141935 (n =
842), and 19361956 (n = 669). Most of the signicance in the
selection gradients we estimated in Tables 13 was contributed
by variation among women in the rst period. The only trait
consistently under signicant selection in all three periods was
age at rst birth (period 1: = 1.120, P = 0.0037; period 2: =
1.107, P = 0.0018; period 3: = 1.488, P = 0.018).

Projecting Evolutionary Change
Table 5 presents the projected changes on the assumption that
conditions will continue to mirror the averages encountered by
this population over the past 60 years. In the next 10 generations
mean TC among women is projected to decline from the average
of 224 over the past 60 years to 216 (209.3222.5) mg/100 mL
(95% C.I.; see Methods). Because the environment has changed
over the past 60 years (Fig. 2) and will continue to change, these
results suggest that whatever changes in environment occur
evolutionary changes will lead to mean cholesterol levels among
women that are 0.8 (0.141.46) mg/100 mL lower in the next
generation than they would be in the absence of evolution.
Similarly, we expect that as a result of evolution, in the next
generation mean body WT among women will increase by 0.2
(0.20 to 0.62) kg then stabilize; HT will decrease a bit, 0.2
(0.030.39) cm; SBP will decrease by 0.25 (0.05 to 0.53)
mmHg; DBP will remain essentially unchanged; blood GLU will
decrease slightly by 0.8 (0.09 to 0.29) mg/100 mL; age at
menopause will increase by 1.0 (0.23 to 2.15) months; and
age at rst birth will decrease by 0.5 (0.6 to 1.7) months. The
rates of projected evolution in haldane units (SD per generation)
range from 0.032 (HT) to 0.002 (DBP), slower than those
Would Unrecorded Early Mortality Have Changed Any of Our
Conclusions?
LRS should be measured from birth to the end of reproduction.
However, we could only study individuals who survived to
adulthood and had measurements on adult traits. During most of
human history, high mortality at early ages was a major factor
driving evolution, but now most children survive well into the
reproductive ages.
To determine whether excluding early deaths from LRS could
have biased our results, we simulated what would happen if a
trait was associated with early death and, therefore, no repro-
duction. For example, we asked what would happen if higher
cholesterol was associated with an increased risk of not surviving
to age 20 and, therefore, remaining childless? What would the
sample look like if we were to include those people who died?
We might see a group of childless women whose adult (never
actually measured) cholesterol levels were on average higher
than other women. We simulated such effects by adding to the
dataset a group of phantom women for two levels of preadult
mortality, 0.011 (survival to age 20, p20 = 0.989, the average for
women in the United States in 2002) and 0.06 (p20 = 0.94, the
average for women in the United States in 19391940) and for

Table 2. Phenotypic variance/covariance matrix

TC, mg/100 mL WT, kg HT, cm SBP, mmHg DBP, mmHg GLU, mg/100 mL MEN BIR

TC 3.860 0.022 0.089 0.336 0.278 0.300 0.180 0.112

WT 0.022 5.710 0.426 1.040 1.070 1.030 0.045 0.040
HT 0.089 0.426 0.266 0.039 0.009 0.023 0.022 0.109
SBP 0.336 1.040 0.039 2.590 1.800 0.688 0.005 0.222
DBP 0.278 1.070 0.009 1.800 1.920 0.399 0.020 0.183
GLU 0.300 1.030 0.023 0.688 0.399 3.570 0.032 0.021
MEN 0.180 0.045 0.022 0.005 0.020 0.032 1.460 0.094
BIR 0.112 0.040 0.109 0.222 0.183 0.021 0.094 5.378

P matrix, log10, all values 1,000. MEN, age at menopause; BIR, age at rst birth.

Byars et al. PNAS | January 26, 2010 | vol. 107 | suppl. 1 | 1789
Table 3. Additive genetic variance/covariance matrix
TC, mg/100 mL WT, kg HT, cm SBP, mmHg DBP, mmHg GLU, mg/100 mL MEN BIR

TC 2.371 0.097 0.126 0.101 0.070 0.022 0.180 0.068 0.108 0.059 0.071 0.080 0.040 0.081 0.095 0.089
WT 0.126 0.101 3.014 0.143 0.376 0.021 0.250 0.079 0.408 0.065 0.329 0.090 0.030 0.100 0.002 0.103
HT 0.070 0.022 0.376 0.021 0.225 0.005 0.020 0.017 0.022 0.015 0.035 0.020 0.027 0.029 0.074 0.024
SBP 0.180 0.068 0.250 0.079 0.020 0.017 1.386 0.066 0.723 0.018 0.454 0.060 0.090 0.064 0.127 0.072
DBP 0.108 0.059 0.408 0.065 0.022 0.015 0.723 0.018 0.950 0.050 0.226 0.055 0.088 0.056 0.173 0.065
GLU 0.071 0.080 0.329 0.090 0.035 0.020 0.454 0.060 0.226 0.055 1.235 0.098 0.040 0.053 0.121 0.080
MEN 0.040 0.081 0.030 0.100 0.027 0.029 0.090 0.064 0.088 0.056 0.052 0.053 0.695 0.084 0.054 0.043
BIR 0.095 0.089 0.002 0.103 0.074 0.024 0.127 0.072 0.173 0.065 0.121 0.080 0.054 0.043 0.537 0.137

G matrix, log10, values 1,000, 1. MEN, age at menopause. BIR, age at rst birth.

each of 10 traits, by giving each phantom individual a value for
the trait equal to the population mean plus 2 SD. For 90% of the
20 cases, the unstandardized values remained in the same
direction, positive or negative, and for 86% of the traits P values
did not change signicance. For example, selection on choles-
terol was always negative and always signicant (20 of 20 cases);
selection on HT was always negative (20 of 20) and almost always
signicant (19 of 20); selection on WT was almost always positive
(18 of 20) and usually signicant (16 of 20); selection on age at
menopause was almost always positive (19 of 20) and almost
always signicant (19 of 20); selection on SBP was usually
positive (17 of 20) but only signicant approximately half the
time (11 of 20); selection on GLU was almost always negative (19
of 20) but rarely signicant (2 of 20); patterns in the other traits
were mixed. Apparently the proportion not surviving to age 20
is so low that if they were in the dataset our major conclusions
would not be likely to change.
Conclusions
Natural selection is acting slowly and gradually on traits of
medical importance and on life history traits in the FHS pop-
ulation. Selection varied in intensity, becoming generally less
intense over time, but not in direction, and it has only operated
consistently over the entire period to reduce age at rst birth.
Predictions for one generation are fairly reliable, but whether
selection will be consistent and sustained enough to bring about
signicant genetic change can only be answered with longer
periods of observation of more traits relevant to human health.
These results suggest slow evolutionary change. It is notewor-
thy, although not surprising, that both age at rst birth and age
at menopause appear to be changing so as to lengthen the
reproductive period, which is consistent with previous ndings
(3). Because fertility is the driving force behind evolution in
modern populations, we might have found larger effects of
evolution on the levels of sex hormones and related traits had
they been measured. The impact of fertility on selection could
prove especially important now that many couples that would
otherwise remain childless can produce offspring with medical
assistance.
The traits we studied were those available from the FHS,
which was focused on heart disease, not reproduction. To better
understand and predict evolutionary changes, the design of
planned large, long-term, multicohort studies should include
input from evolutionary biologists and, in particular, should
consider measuring traits that might be closely associated with
reproductive success.
Methods
The FHS continues today. Study design and entry criteria for the FHS are
detailed in Dawber et al. (14) and Kannel et al. (15). We included subjects from
the original and offspring cohorts; they received physical examinations and
questionnaires administered by trained interviewers every 2 and 34 years,
respectively. The Institutional Review Board requirements have been ade-
quately addressed for all of the participants in the FHS, and formal approval
for the data used was obtained from the dbGaP (www.ncbi.nlm.nih.gov/sites/
entrez?Db = gap).
Relative Fitness. We calculated LRS for women who reported at a postmeno-
pausal age how many live births they had had. Of the 5,372 women in the
original and offspring cohorts, 739 were removed because of missing values
for menopause (or menopause had not been reached) and 852 were removed
because the number of live births was not recorded after a postmenopausal
age. Sample size was further reduced to 3,224 after excluding an additional
557 women who reached menopause unnaturally (e.g., ovaries removed,
hysterectomy, radiation, chemotherapy) before the age of 45 and to 2,238

Table 4. Selection gradients acting on women in the Framingham population (combined dataset, women born between 1892 and
1956)
Trait N SD P % linear % Quad

TC, mg/100 mL 2,227 223.2 48.2 0.743 1.447 0.0011 0.295

HT, cm 2,227 160.7 6.4 3.999 6.672 0.0002 0.689
WT, kg 2,227 65.7 13.3 0.861 0.985 <0.0001 0.197 0.394
SBP, mmHg 2,227 127.2 22.1 0.963 1.545 0.0236 0.019
DBP, mmHg 2,227 79.1 11.9 0.982 1.317 0.0724 -
GLU, mg/100 mL 2,227 89.6 22.8 0.848 0.548 0.0596 - 0.492
Diabetes 2,227 - - 0.076 0.008 0.3473 -
Age at rst birth 1,448 26.5 4.6 1.267 1.758 <0.0001 *
Age at menopause 2227 49.2 4.1 1.280 2.839 0.0035 0.689 0.098

Associations with age at rst birth were estimated only for women who reported at least one live birth. N, sample size of individual women; , mean; ,
unstandardized directional selection gradient from a multiple linear regression model that included interaction and quadratic terms; , mean standardized
selection gradient; P, signicance estimates from the Poisson model; %, percentage of variation in lifetime reproductive success explained. Presenting the mean
and SD for diabetes would be inappropriate because it was recorded as presence/absence.*, The percentage of variation in lifetime reproductive success
explained by age at rst birth is not strictly comparable to that explained by the other traits because the sample was smaller; in that separate analysis it explained
5%. One covariate, level of education, was signicant; it explained 0.295% of the variation in lifetime reproductive success. Only one of the 45 two-way
interaction terms was signicant, estrogen therapy diastolic blood pressure; it explained 0.197% of the variation in lifetime reproductive success.

1790 | www.pnas.org/cgi/doi/10.1073/pnas.0906199106 Byars et al.

Table 5. Projected evolutionary change, untransformed values
TC, mg/100 mL WT, kg HT, cm SBP,mmHg
Generation
0 223.9 64.7 160.2 127.6
5 219.8 1.58 65.4 0.58 159.3 0.41 126.3 0.71
10 215.9 3.35 65.6 1.33 158.1 0.90 125.2 1.47
% 3.6 1.4 1.3 1.9
Haldanes 0.016 0.007 0.032 0.010
The averages for generation 0 are those observed for the Framingham original and offspring cohorts between the ages of 20 and 60 over the years 19552003.
Values for later cohorts are the means that would be expected given the average conditions over the period of observation and evolutionary change. %, percent
change in traits from generation 0 to 10. Haldanes: rate of evolution in SD per generation.
after excluding those who had been measured <3 times for any of the
continuous traits. Accuracy of LRS estimates was improved by using the FHS
pedigree le (and other data) to correct for number of live births >5. Twenty-
four women (1.0%) who had ve or more live births were recorded as having
had ve as part of the deidentication of the data. We estimate that 7 of
those 24 women actually had more than the ve births (generally only one
more) indicated by the dataset; we recorded all 24 as having had ve births.
Main Phenotypes. We used some traits known to be associated with cardio-
vascular disease. They included TC, WT, HT, SBP, DBP, and serum GLU. TC
included both serum (earlier survey rounds) and plasma (later) measures; both
were treated as one here. Blood pressure was measured twice in each exam-
ination; only the rst physicians measure was used here. Methods for the
various cholesterol measures throughout the study have been described
(16, 17).
For both cohorts, WT, HT, SBP, DBP, and GLU were measured from exam-
ination 1 (1948 and 1971 onward for original and offspring cohorts, respec-
tively). Number of measures per trait varied depending on how many exams
a woman attended throughout the study.
We found complex nonlinear changes in traits with age and year of
measure that may reect demographic and developmental changes through-
out the study period and a womans life. We removed these effects by taking
residuals from a 3D surface of a generalized additive model of each trait by
age and year of measure, then converted these back into the original metric
by adding the overall trait mean (Fig. 2). We used measures across the ages of
2060, which span the reproductive years of modern human women, and only
included women with three or more measures for each trait, because there is
considerable intraindividual trait variation over time (18, 19). Residuals were
then averaged to obtain one point per trait per woman and log-transformed
to correct for deviations from normality.
Because traits may be affected by number of offspring (e.g., women might
gain WT with number of births), thereby potentially confounding the covaria-
tion between traits and tness, we compared traits measured at an age when
women had not yet reproduced (according to age at rst birth estimates from
the FHS pedigree) or at the earliest age a trait was measured (up to the age of
30), to the same traits measured at an age when women in the sample had
completed fertility (between the ages of 45 and 55). We found no signicant
difference in an ANOVA for any of the traits examined, suggesting few, if any,
cumulative effects of number of offspring on the traits examined.
Covariates. Demographic covariates included level of education and whether
foreign or native born. We assumed that women from the offspring cohort
were all born in the United States. Education was coded as number of years of
education completed; the few women with missing values here were assumed
to have a minimum of 8 years of education.
Other covariates included self-reported use of cholesterol-lowering med-
ication (e.g., statins, brates, resins), self-reported use of medication for
hypertension or high blood pressure, presence or absence of diabetes mellitus,
self-reported smoking status, and estrogen use (hormone therapy or contra-
ceptive use), which can affect cholesterol levels (20), other traits (21, 22), and
womens LRS. We only used information on medication use across the ages of
2060. Smoking status was recorded as whether a woman was or had been a
smoker. Of the remaining 2,238 women, only 11 (or 0.49%) were recorded as
having taken cholesterol-lowering medication between the ages of 20 to 60;
they were removed from the dataset, yielding a nal sample size of 2,227. All
covariates (except smoking intensity and education level) were coded as
binary (present/absent) in the multiple regression analyses.
Byars et al.
DBP, mmHg GLU, mg/100 mL Age at menopause Age at rst birth
78.5 89.1 48.9 26.18
78.6 0.34 88.4 0.52 49.3 0.23 25.96 0.23
78.7 0.73 88.1 1.03 49.7 0.51 25.74 0.48
0.3 1.1 1.6 1.7
0.002 0.004 0.020 0.010
Projections. We estimated the effect of directional selection on the mean
value of each trait in the population in the next generation (the response to
selection) with this equation:
z = G:
z is a vector of predicted changes in the population means of characters
between the observed and next generation, G is the additive genetic variance-
covariance matrix, and is a vector of the selection gradients. Predicted
changes in trait means should be interpreted cautiously for the direction and
intensity of selection and the additive genetic variances and covariances all
change over time and across generations.
To estimate the cumulative effect over several generations, we projected
the mean change between generations using the equation z = G = GP1
s, where P is the phenotypic variance-covariance matrix and s is the vector of
changes in the traits that would occur in one generation as a result of selection
alone. The change between generations in the variancecovariance matrix for
traits was then estimated as P* P = PP ssT, where is the matrix of
interaction terms among the traits calculated from the coefcient estimates
from a linear regression (7). We assumed that G, s, and remain xed across
generations.
Condence Intervals for Projections. The condence intervals for the pro-
jection reect the uncertainty in the , , and G matrixes by using Monte
Carlo simulations. Random number generators were used to run 5,000
projections with different estimates for each parameter. The and were
handled simultaneously by using a multinomial random number generator
and the matrix of variances and covariances among the regression coefcients
(including the intercept). The coefcients on the linear and quadratic terms were
then used to set up and . Each element of the G matrix was handled
separately by using a random number generator and the standard errors
produced by SOLAR (24). The projections were all done on the log of traits.
Statistical Analysis. LRS from women measured for TC, WT, HT, SBP, DBP, GLU,
age at menopause, age at rst birth, age at death, and level of education were
used to assess whether these traits inuenced womens tness. Multiple linear
regression was used to infer the strength and direction of selection, and
multiple Poisson regression was used to test statistical signicance.
We adjusted LRS to account for uctuations in fertility over time (Fig. 2)
relative to women in the same birth cohort (birth years 18921918, 1919
1925, 19261936, 19371941, 19421946, 19471956). Relative tness was
calculated by dividing each woman's number of births by the mean for her
birth cohort. The Poisson models included binary markers for each cohort. We
rst used education level, smoking, and country of birth as controls to remove
their potentially confounding effects on LRS. When we then assessed selection
on cultural traits, we included education level and smoking as covariates. In all
analyses we included quadratic terms for the main traits (TC, WT, HT, SBP, DBP,
GLU, age at menopause, age at rst birth) and two-way interactions between
traits and covariates. Quadratic coefcients were doubled to estimate stabi-
lizing/disruptive selection gradients (23). Coefcients from the multiple linear
regressions were standardized by using trait means [see Hereford et al. (9)].
Partial regression coefcients, termed directional selection gradients (),
estimate the magnitude of directional selection on a trait i, with the effects of
selection on all of the other measured traits removed.
G Matrix Estimates. We used average residuals (described above) to control for
changes in heritability over time and age. Additive genetic variance and
covariance estimates were made with a pedigree-based maximum-likelihood
PNAS | January 26, 2010 | vol. 107 | suppl. 1 | 1791
method implemented in SOLAR (24). Signicance was determined by like-
lihood ratio tests.
ACKNOWLEDGMENTS. We thank the National Evolutionary Synthesis Center
for support and the other members of our National Evolutionary Synthesis
Center working group (Charles Goodnight, David Houle, Martin Larson, Trudy
1. Tait L (1869) Has the law of natural selection by survival of the ttest failed in the case
of man? Dublin Q J Med Sci 47:102113.
2. Bynum WF (1983) Darwin and the doctors: Evolution, diathesis, and germs in 19th
century. Gesnerus 40:4353.
3. Kirk KM, et al. (2001) Natural selection and quantitative genetics of life-history traits
in Western women: A twin study. Evolution (Lawrence, Kans) 55:423435.
4. Govindaraju DR, et al. (2008) Genetics of the Framingham Heart Study population. Adv
Genet 62:3365.
5. Kingsolver JG, et al. (2001) The strength of phenotypic selection in natural populations.
Am Nat 157:245261.
6. Robertson A (1966) A mathematical model of culling process in dairy cattle. Anim Prod
8:95108.
7. Lande R, Arnold SJ (1983) The measurement of selection on correlated characters.
Evolution (Lawrence, Kans) 37:12101226.
8. Janzen FJ, Stern HS (1998) Logistic regression for empirical studies of multivariate
selection. Evolution (Lawrence, Kans) 52:15641571.
9. Hereford J, Hansen TF, Houle D (2004) Comparing strengths of directional selection:
How strong is strong? Evolution (Lawrence, Kans) 58:21332143.
10. Brown WM, et al. (2002) Age-stratied heritability estimation in the Framingham
Heart Study families. BMC Genet 4(Suppl 1): S32.
11. Mathias RA, et al. (2002) Comparison of year-of-exam and age-matched estimates of
heritability in the Framingham Heart Study data. BMC Genet 4(Suppl 1): S36.
12. Kohler HP, Rodgers JL, Christensen K (1999) Is fertility behavior in our genes? Findings
from a Danish twin study. Popul Dev Rev 25:253288.
13. Hendry AP, Kinnison MT (1999) PerspectiveThe pace of modern life: Measuring rates
of contemporary microevolution. Evolution (Lawrence, Kans) 53:16371653.
14. Dawber TR, Kannel WB, Lyell LP (1963) An approach to longitudinal studies in a
community: Framingham Study. Ann NY Acad Sci 107:539556.
1792 | www.pnas.org/cgi/doi/10.1073/pnas.0906199106
Mackay, Shamil Sunyaev, Anatoli Yashin, and Sebastian Zoellner) for helpful
comments. D.E. was supported by National Institutes of Health (National
Institute on Aging) Grant P30 AG12836, the Boettner Center for Pensions and
Retirement Security at the University of Pennsylvania, and National Institutes
of Health (National Institute of Child Health and Development Population
Research Infrastructure Program) Grant R24 HD-044964.
15. Kannel WB, et al. (1979) Investigation of coronary heart disease in families: Framing-
ham offspring study. Am J Epidemiol 110:281290.
16. Abell LL, Levy BB, Brodie BB, Kendall FE (1952) A simplied method for the estimation
of total cholesterol in serum and demonstration of its specicity. J Biol Chem 195:357
366.
17. Warnick GR, Benderson J, Albers JJ (1982) Dextran sulfate Mg2+ precipitation procedure
for quantitation of high-density-lipoprotein cholesterol. Clin Chem 28:13791388.
18. Frishman WH, et al. (1992) Serum lipids and lipoproteins in advanced age: Intraindi-
vidual changes. Ann Epidemiol 2:4350.
19. Bookstein L, Gidding SS, Donovan M, Smith FA (1990) Day-to-day variability of serum
cholesterol, triglyceride, and high-density-lipoprotein cholesterol levels: Impact in the
assessment of risk according to the National Cholesterol Education Program Guide-
lines. Arch Intern Med 150:16531657.
20. Demissie S, et al. (2006) Estrogen receptor- variants are associated with lipoprotein
size distribution and particle levels in women: The Framingham Heart Study. Athero-
sclerosis 185:210218.
21. Fox CS, et al. (2005) Sex-specic association between estrogen receptor- gene varia-
tion and measures of adiposity: The Framingham Heart Study. J Clin Endocrinol Metab
90:62576262.
22. Peter I, et al. (2005) Variation in estrogen-related genes and cross-sectional and
longitudinal blood pressure in the Framingham Heart Study. J Hypertens 23:2193
2200.
23. Stinchcombe JR, et al. (2008) Estimating nonlinear selection gradients using quadratic
regression coefcients: Double or nothing? Evolution (Lawrence, Kans) 62:24352440.
24. Blangero J, Almasy L, Dyer T, Peterson C (1999) Sequential oligogenic linkage analysis
routines: SOLAR (Solar Software, Westerville, OH), Version 4.2.0. Available at http://
solar.sfbrgenetics.org/.
25. Schluter D, Nychka D (1994) Exploring tness surfaces. Am Nat 143:597616.
Byars et al.